This invention relates to steroidal glycosides and methods of using the same, particularly as hypocholesterolemic agents and antiatherosclerosis agents, in mammals.
Many known products possessing hypocholesterolemic activity are cross-linked synthetic polymer derivatives, for example of polystyrene. For example, cross-linked, water-insoluble, bile-acid-binding polystyrene-based resins, e.g., Cholestyramine.RTM. agents, have a gritty "mouth-feel", and thus have poor palatability. In addition, these resin beads typically have a low in vivo efficiency. Thus, the effective hypocholesterolemic dose of these materials is excessive, typically 18-24 grams of formulated product per day. Other known polymers having hypocholesterolemic activity include the natural product chitosan and chitosan derivatives as described in European Application pub. no. 0212145. However, the effective hypocholesterolemic dose of these materials is also high.
Other known hypercholesterolemia controlling agents include plant extracts such as "alfalfa saponins". However, these plant extracts are of variable composition and contain significant amounts of nonuseful chemical substances. Due to the variations in composition, it is difficult to set a standard dosage or predict the impurities present. Thus, such extracts are not well suited for use by humans. Furthermore purification of these extracts would be expensive. As an alternative certain synthetically produced, pure "sapogenin-derived" compounds e.g., substances compounded from spirostane, spirostene or sterol-derived compounds depress cholesterol absorption more effectively than alfalfa extracts on a weight basis and thus can be administered in reasonable sized doses. Because the chemical compositions of these substances are known and because they can be synthesized at a high degree of purity, they are suitable for use by any warm-blooded animal, including humans.
However, unless administered in massive mounts, pure sapogenins do not significantly inhibit cholesterol's absorption. It is only when compounded with another moiety that sapogenins have the desired effect. Examples of such sapogenin compounds are compounds of tigogenin and diosgenin, particularly glycosides thereof. P. K. Kintia, Iu. K. Vasilenko, G. M. Godanu, V. A. Bobeiko, I. V. Suetina, N. E. Mashchenko, Kim. Pharm. Zh., 1981, 15(9), 55 discloses 3-O-(.beta.-D-galactopyranosyl)hecogenin and its use as a hypocholesterolemic agent. U.S. Pat. Nos. 4,602,003 and 4,602,005 disclose certain steroidal glycosides, in particular 3-O-(.beta.-D-glucopyranosyl)tigogenin and 3-O-(.beta.-D-cellobiosyl)tigogenin and their use for the control of hypercholesterolemia. 3-O-(.beta.-D-cellobiosyl)tigogenin has superior hypocholesterolemic activity when compared to, for example, cholestyramine.
In addition, certain other steroidal glycosides described below have been published, however these publications do not address hypocholesterolemic activity. "Structural Features of the Antioxidant and fungicidal Activity of Steroid Glycosides", Dimoglo, A. S.; Choban I. N.; Bersuker, I. B.; Kintya, P. K.; Balashova, N. N.; Bioorg. Khim, 11 (3), 408-413, 1985 discloses rockogenin .beta.-D-galactopyranoside and tigogenin .beta.-D-lactoside. "Preparation and Properties of Some New Steroid .beta.-D-Glucopyranosides, .beta.-D-Glucopyranosiduronic Acids, and Derivatives", Schneider, J. J.; Carb. Research, 17, 199-207, 1971 discloses tigogenin .beta.-D-glucopyranuronoside. "Sterol Glycoside with Activity as Prostaglandin Synthetase Inhibitor", Pegel, K. H. Walker, H.; U.S. Pat. No. 4,260,603, Apr. 7, 1981 discloses hecogenin .beta.-D-glucopyranoside. "Hemolytic Properties of Synthetic Glycosides", Segal, R.; Shud, F.; Milo-Goldzweig, I.; J. Pharm. Sci. , 67 (11) 1589-1592, 1978 discloses tigogenin .beta.-D-maltosside, tigogenin .beta.-L-fucopyranoside smilagenin .beta.-maltoside and tigogenin .alpha.-L-rhamnoside. "Steroid Glycosides from the Roots of Capsicum annuum II: The Structure of the Capsicosides", Gutsu, E. V.; Kintya, P. K.; Lazurevskii, G. V.; Khim. Prir. Soedin., (2), 242-246, 1987 discloses tigogenin .alpha.-D-arabanopyranoside and tigogenin .beta.-D-galactopyranoside. "Molluscicidal Saponins from Cornus Florida L.", Hostettmann, K.; Hostettmann- Kaldas, M.; Nakanishi, K.; Helv. Chim. Acta, 61, 1990-1995, 1978 discloses smilagenin .beta.-D-galactopyranoside. "Steroidal Saponins from Several Species of Liliifiorae Plants", Yang, C.; Li, K.; Ding, Y.; Yunnan Zhiwu Yanjiu Zengkan, Suppl. 3, 13-23, 1990 discloses (25S)-hecogenin cellobioside. "Determination of the Absolute Configuration of a Secondary Hydroxy Group in a Chiral Secondary Alcohol Using Glycosidation shifts in Carbon-13 NMR Spectroscopy", Seo, S.; Tomita, Y.; Tori, K.; Yoshimura, Y.; J. Am. Chem. Soc. , 100(11), 3331-3339, 1978 discloses smilagenin .beta.-glucoside and smilagenin .alpha.-glucoside. "Steroid Glycosides from Asparagus officinalis", Lazurevskii, G. V.; Goryanu, G. M.; Kintya, P. K.; Dokl. Akad. Nauk. SSSR, 231(6), 1479-81, 1976 discloses sarsasapogenin .beta.-glucoside.
Although the hypocholesterolemic compounds described above make a significant contribution to the art there is a continuing search in this field of art for improved hypocholesterolemic pharmaceuticals.